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54310.2217/17460816.3.6.543 © 2008 Future Medicine ISSN 1746-0816Future Rheumatol. (2008) 3(6), 543–558

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Oral manifestations of Sjögren’s syndrome

Carol M Stewart† & Kathleen Berg†Author for correspondence: University of Florida Center for Orphaned Autoimmune Disorders, PO Box, 100414 JHMHC, University of Florida College of Dentistry, Gainesville, FL 32610, USA n Tel:. +1 352 392 6775 n Fax: +1 352 392 2507 n [email protected]

Sjögren’s syndrome is a chronic autoimmune disease complex characterized by inflammation of the exocrine glands, primarily resulting in keratoconjunctivitis sicca, hyposalivation and xerostomia, or dry mouth. Dry mouth is one of the most easily recognized components and may lead the clinician to diagnosis. Hyposalivation is more than an inconvenience, having a significant adverse effect on health and quality of life. Early recognition of this condition may minimize some of the adverse sequelae. A dental evaluation in patients with confirmed or suspected Sjögren’s is recommended. The focus of this review article is to highlight oral manifestations of Sjögren’s syndrome to include pathogenesis, clinical presentation, implications for health, diagnostic tools, management strategies and future perspectives.

Keywords

dry mouth n hyposalivation n Sjögren’s syndrome n xerostomia

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Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://cme.medscape.com/public/futuremedicine; (4) view/print certificate.

Learning objectivesUpon completion of this activity, participants should be able to:

List the clinical features of Sjögren’s syndrome (SS)n

Describe the prevalence of extraglandular manifestations of SSn

Identify other conditions associated with SSn

Describe the diagnostic criteria of the European–American Consensus Group for SSn

Identify infections of concern in patients with SSn

Financial & competing interests disclosureCME AuthorDésirée Lie, MD, MSEd, Clinical Professor, Family Medicine, University of California, Orange, CA, USA; Director, Division of Faculty Development, UCI Medical Center, Orange, CA, USADisclosure: Désirée Lie, MD, MSEd, has disclosed no relevant financial relationships.EditorElisa Manzotti, Editorial Director, Future Science Group, London, UK.Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.Authors & CredentialsCarol M Stewart, MS, DDS, MS, University of Florida Center for Orphaned Autoimmune Disorders, University of Florida College of Dentistry, FL, USA Disclosure: Carol M Stewart, MS, DDS, MS, has disclosed no relevant financial relationships.Kathleen Berg, PhD, University of Florida Center for Orphaned Autoimmune Disorders, University of Florida College of Dentistry, FL, USA Disclosure: Kathleen Berg, PhD, has disclosed no relevant financial relationships.

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Future Rheumatol. (2008) 3(6)544 future science group

Review Stewart & Berg

Sjögren’s syndrome (SS) is a common, progres-sive autoimmune rheumatic disease character-ized by subjective dry mouth (xerostomia), dry eyes (keratoconjunctivitis sicca) and extreme fatigue. B- and T-cell lymphocytic infiltration of the exocrine glands leads to diminished salivary and lacrimal and gland function. Symptoms may be limited to a local effect on the salivary and lacrimal glands, or extend to include wide-spread involvement of multiple organ systems [1,2]. SS may impact the peripheral and central nervous system, muscles, bone marrow, joints, kidneys, pancreas, thyroid and other glands. Research indicates that systemic extra glandular manifestations, including lymphoma, may appear in 40% of individuals with primary SS and present in two ways: the development of lymphoepithelial lesions in several extra-exo-crine gland tissues (i.e., bronchi, renal tubules or biliary ducts); and vasculitis related to the deposition of immune complexes due to B-cell hyperreactivity [3].

The disorder may occur alone (primary SS), or in combination with another rheumatic disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma or pri-mary biliary cirrhosis, in which case it is classified as secondary SS. The disease affects women more frequently than men, with a reported female:male ratio of 9:1 [4]. A recent report from a Hungarian cohort indicated a higher involvement in men than previously reported, with a female:male ratio of 7:1 [5]. Although it has been described in children and adolescents [6,7], the onset of symp-toms occurs most often during middle age [8]. Currently, the etiology of SS is not clearly under-stood, but appears to be multi factorial. It has been suggested that environ mental agents may trigger SS in genetically predisposed individuals. Potential mechanisms underlying SS include dis-turbances in apoptosis [9–12], circulating autoanti-bodies against the ribonucleo proteins Ro and La [13,14] or cholinergic muscarinic receptors [15–17] in salivary and lacrimal glands, or cytokines [18].

These processes interfere with normal glandular function, and as the mucosal surfaces become sites of chronic inflammation, the disease appears to enter a self-perpetuating inflammatory cycle.

Depending on the classif ication criteria applied, estimates of its prevalence in the adult population range from 0.5 to 3% [19], making it one of the most common autoimmune dis-orders. However, due to the vague and diverse presentation of initial symptoms, the diagnosis is difficult and often takes several years. It is of utmost importance for all clinicians to be vigilant

regarding the oral manifestations of SS, as the disease often manifests with initial complaints of ‘dry mouth’ and related oral complaints. The concerns of oral dryness, increase in dental resto-rations and crowns, oral ulcers and lack of taste and appetite, may be attributed to etiologies such as stress, dehydration, inadequate oral hygiene and medications, without a consideration of SS. The astute physician can provide proper patient education and necessary referral consultations to minimize the debilitating consequences of untreated oral complications of SS.

Diagnostic criteriaSeveral diagnostic protocols have been devel-oped and revised as more is learned. To date, the American–European Consensus Group (AECG) 2002 classification criteria appear to be most universally accepted (Box 1) [20]. The AECG criteria require the presence of four of six criteria, which include objective criteria, oral and ocular symptoms, and either positive serum autoantibodies Ro/SS-A and/or La/SS-B or positive histopathology from a labial salivary gland biopsy.

Oral symptomsAs indicated in Box 1, oral symptoms include xerostomia for greater than 3 months and frequent water intake. To assist assessment of subjective dry mouth, positive responses to the following questions are very useful: the need to drink water to swallow foods, the need to keep a glass of water by the bed or frequent awaken-ing at night due to oral dryness, the amount of saliva in the mouth feels inadequate, and difficulty speaking [21,22].

Saliva is secreted from three major paired glands (parotid, submandibular and sublingual) and from hundreds of minor salivary glands located throughout the submucosa of the oral cavity, with the exception of the anterior hard palate and gin-giva. Stimulated saliva, produced during eating, is controlled by the autonomic nervous system. It aids chewing of food, formation and swallowing of a food bolus and digestion via the enzymes amylase and lipase. The parotid gland, which pro-vides thin watery secretions, contributes signifi-cantly to stimulated saliva. Saliva secreted in the absence of apparent sensory stimuli related to eat-ing is referred to as resting or unstimulated saliva. The parotid gland contributes 25% to unstimu-lated flow. The submandibular gland, a mixed mucous and serous gland, contributes 60%, and the sublingual and minor mucous glands each contribute 7–8% of whole saliva [23–25].

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Oral manifestations of Sjögren’s syndrome Review

A continuous production of small amounts of saliva occurs throughout the day, often from the minor salivary glands in response to dry-ness of the oral mucosa and stimulation from movements of the jaw and tongue. This fluid covers the oral and pharyngeal cavities and is responsible for maintaining the integrity of the mucosa. As little time is spent eating during a 24-h period, resting saliva is a sig-nificant contributor to total salivary output. A lack of unstimulated saliva is a key factor in the sensation of dry mouth [26].

Easily recognized clinical indications of a diminished salivary output could include dry and /or chapped lips, salivary gland enlarge-ment, lipstick on the anterior teeth, a lack of pooling in the floor of the mouth, thick or frothy saliva and examination gloves sticking to the tongue or buccal mucosa. Upon closer examination, the clinician might also observe signs of candidiasis. Multiple restorations, crowns and often decay at the cervical portion of the tooth, either just above the gingiva or on the root surfaces, can be observed (Figure 1). The tongue might appear fissured, slightly erythematous and/or depapillated, as shown in Figure 2. This clinical presentation is similar to the dorsal tongue appearance in a patient with vitamin B12 deficiency, which should be ruled out. Box 2 contains a list of clinical signs and symptoms of SS.

Objective salivary gland involvement SialometryIn SS, both quantitative and qualitative changes in saliva often develop early in the disease. The normal unstimulated whole salivary flow rate ranges from 0.3 to 0.4 ml/min, but the range is wide [27,28]. According to the AECG criteria for SS, severe hyposalivation is an unstimulated salivary flow rate of less than 0.1 ml/min. This represents an approximate reduction of 50–70% below normal.

To accurately measure the whole unstimulated salivary flow rate, it should be collected under stan-dard conditions and calculated gravi metrically. Patients should refrain from oral hygiene proce-dures, smoking, eating and drinking for at least 2 h prior to the test session. Seated comfortably in an upright position, patients are instructed to allow their saliva to flow (drool) into a preweighed vessel for a period of 15 min. Sealed containers are then reweighed to determine the weight of saliva expectorated. The unstimulated salivary flow rate is determined by gravitation, using a scale with an accuracy to 0.01 g. Presuming

that 1 g of saliva is equivalent to 1 ml, the mea-sured volume is expressed as flow rate in ml per min [29,30]. While gravimetric ana lysis for whole unstimulated salivary flow rate might be cumber-some and too time-consuming for a busy practice, asking the patient to expectorate or ‘drool’ into a calibrated tube or cup for 10 min, as opposed to 15 min without stimulation, could be help-ful. If the patient failed to produce enough saliva to meet the 1.0 ml designation on the container in 10 min, further assessment for hyposalivation would be indicated.

Box 1. European–American Consensus Group Criteria for Sjögren’s syndrome.

I. Ocular symptoms (positive response to at least one of three)Daily, persistent, troublesome eyes for more than 3 monthsn

Recurrent sensation of sand or gravel in the eyesn

Use of tear substitutes more than three times per dayn

II. Oral symptoms (positive response to at least one of three)Daily feeling of dry mouth for more than 3 monthsn

Recurrently or persistently swollen salivary glands as an adultn

Frequent drinking of liquids to aid in swallowing foodn

III. Ocular signs (positive result for at least one of two tests)Schirmer’s test, performed without anesthesia (n ≤5 mm in 5 min)

Rose Bengal score or other ocular dye score (n ≤4 according to van Bijsterveld’s scoring system)

IV. Histopathology in minor salivary gland biopsyFocal lymphocytic sialoadenitis, with focus score n ≥1 (a focus is defined as ≥50 lymphocytes per 4 mm2 of glandular tissue adjacent to normal appearing mucous acini)

V. Salivary gland involvement (positive result for at least one of three)Unstimulated whole salivary flow (n ≤1.5 ml/15 min)

Parotid sialography showing the presence of diffuse sialectasis (punctuate, n

cavitary or destructive pattern), without evidence of obstruction in the major ducts

Salivary scintigraphy showing delayed uptake, reduced concentration and/or n

delayed excretion of tracer

VI. Autoantibodies Presence in the serum of antibodies to Ro(SS-A) or La(SS-B) antigens, or bothn

Classification criteriaPrimary Sjögren’s syndrome n

– The presence of any four of the six items, as long as either item IV (histopathology) or item VI (serology) is positive – The presence of any three of the four objective criteria (Items III, IV, V and VI)

Secondary Sjögren’s syndrome n

– In the presence of another connective tissue disease, the presence of item I or item II, plus any two from items III, IV and V

Exclusion criteria n

– Past head and neck radiation treatment – Hepatitis C infection – AIDS – Pre-existing lymphoma – Sarcoidosis – Use of anticholinergic drugs (since a time shorter than fourfold the half-life of the drug)

Adapted from [20].



Additional salivary gland collection tech-niques are available for measuring specific glandular secretions. Modified Lashley cups (Carlson–Crittenden cups) may be applied over Stenson’s duct for collection of pure parotid gland saliva. For obtaining saliva from the sub-mandibular and sublingual glands, syringe aspiration from Wharton’s duct and Rivinus’s ducts may be accomplished as well. Separate aspiration is challenging in clinical practice due to the close anatomical location of the sub-

mandibular and sublingual gland orifices and the common presence of communicating ducts between the submandibular and sublingual main ducts [31,32].

ImagingIn addition to unstimulated whole sialometry, objective evidence of salivary gland involvement may also be obtained using imaging techniques. A salivary scintigraphy using radio active techne-cium-99m pertechnetate (Tc99) will assess gland function and show delayed uptake, reduced con-centration and/or delayed excretion of tracer. A parotid sialogram may be performed using water-based radiocontrast dye injected into the Stenson’s duct. Using conventional radiography, sialographic findings may reveal punctuate sia-lectasia and glandular atrophy. Abnormal filling defects diffusely distributed throughout glands may be seen. Due to the possibility of infec-tion and blockage in the ducts, conventional sialography is used less frequently in contem-porary practice. Modern imaging modalities, such as magnetic resonance sialography, allows visualization of the salivary duct system to the tertiary branches, and can be a useful, non-invasive method for assessment of complaints of dry mouth [33,34]. Renewed attention is being given to the use of ultrasonography for diagnos-tic purposes in patients with primary SS. It pro-vides a noninvasive method to assess structural changes to salivary glands during inflamma-tion [35]. A recent report found the detection of reduced volumes of both submandibular glands in patients with primary and secondary SS had a specificity of 93% and a sensitivity of 48% at the cut-off point of 3.0 ml. Of note, the volume of the parotid glands did not differ between the groups of patients [36].

Labial salivary gland biopsyThe labial salivary gland biopsy is performed on normal-appearing mucosa of the lower lip between the midline and commissure. Five or more accessory salivary gland lobules are exam-ined histopathologically for the presence of focal chronic inf lammatory aggregates. A cluster of 50 or more lymphocytes with some plasma cells is called a focus. The numbers of foci in a 4 mm2 tissue section constitute the focus score. A characteristic histopathologic feature in minor salivary glands in SS is focal lymphocytic sialad-enitis, as depicted in Figure 3. The foci are found adjacent to normal-appearing acini throughout the glands, and are often periductal [37,38]. For the current AECG criteria, a finding of one or

Figure 1. Tongue and dentition of primary Sjögren’s patient. This photograph shows fissuring of tongue, advanced decay on the root surface (white arrow), recession and early root decay (blue arrow), five crowns (black arrow), and an edentulous space in the mandibular anterior, indicative of tooth loss.

Figure 2. Dorsal tongue in primary Sjögren’s syndrome patient showing central depapillation, dryness and erythema.



more foci within a 4 mm2 area of glandular tis-sue is supportive of the SS diagnosis. Complete destruction of glandular acini, extensive fibrosis and dilated ducts would be more consistent with chronic sclerosing sialadenitis, not supportive of a SS diagnosis (Figure 4).

Currently, the labial salivary gland biopsy is considered the most reliable oral diagnostic test for confirmation of SS. However, clinicians are becoming increasingly aware that the labial salivary gland biopsy is not completely reli-able, due to the potential for false-positive and false-negative results. In the past few years, the accuracy of the biopsy interpretation, impact on disease classification and diagnostic benefits of this procedure have been reviewed with mixed findings [39–42]. It is recognized that lympho-cytic foci may be seen in non-SS patients, nor-mal patients and as part of the aging process [43–46]. In addition, false-negative biopsies may be reported if inadequate tissue is obtained, or a sampling error occurs based on location.

Conversely, several studies report that signifi-cant focal infiltrates will not be present unless a connective tissue disease is present [47–49]. Previous studies examining the relationships among clinical, laboratory and histopatho-logical findings in SS patients have shown vary-ing results. While a number of investigators have reported significant correlations between biopsy findings and serological or salivary mea-sures [50–52], others have found no relationship between these variables [53,54]. Some studies indi-cate that the lymphocytic infiltration in minor salivary glands, measured as a focus score, will increase over time [55]. In addition, it has been reported that, in SS patients, the highest focus scores belong to those with lowest whole unstim-ulated salivary flow rate [56]. It is interesting to note that focus scores are reported to be lower in SS patients who are cigarette smokers [57].

AutoantibodiesOne of the main diagnostic tools for SS is the presence of circulatory autoantibodies to 60 kDa Ro/SS-A and La/SS-B. Antibodies occur in approximately 60–70% of patients with SS. Studies have suggested that levels of anti-60-kDa Ro and anti-La are correlated with earlier onset, longer disease duration, recurrent parotid gland enlargement and more intense lympho-cytic infiltration of the minor salivary glands and extraglandular manifestations [4,58].

Recent studies have assessed correlations between salivary production and autoanti-body profile. The anti-La titer was significantly

associated with salivary production rate, after age correction. Salivary production was greater in the group with anti-Ro alone than in the group with both positive anti-Ro and anti-La titers [59].

Impact of hyposalivation on health & quality of life

Significant salivary componentsProtection against bacterial, viral and micro-bial agents is provided by enzymes and anti-microbial fluids. Enzymes such as lysozyme and peroxidase have antimicrobial and antiviral properties. Histidine-rich proteins, histatins, have strong anticandidal effects. Proline-rich proteins, which comprise a significant compo-nent of parotid saliva, have roles in lubrication and development of pellicle on the surface of teeth, which acts to reduce frictional wear. Immunoglobulins help protect the integrity of the oral mucosa as well.

Salivary electrolytes provide critical buffer-ing and remineralization activities. Calcium, phosphate, bicarbonate and fluoride are of par-ticular importance for oral health. The criti-cal pH for saliva is 5.5–6.5. Below that pH, tooth enamel may demineralize. This process is inversely related to the concentrations of cal-cium and phosphate in the saliva [60]. Saliva is super saturated with respect to hydroxyapa-tite, the main mineral of teeth. Thus, tooth enamel bathed with normal saliva is resistant

Box 2. Clinical signs & symptoms of Sjögren’s syndrome.

Xerostomia, usually with hyposalivationDysgeusian

Dysphagian

Dry, chapped lipsSalivary gland enlargement

Unilateral or bilateraln

Sometimes chronic once presentn

TongueFissured, erythematousn

Depapillatedn

High rate of dental decay Caries at cervical 1/3 of tooth and/or incisal edgesn

Heavily restored dentition with restorations and/or crownsn

HalitosisCandidiasis

Erythematous candidiasis n

– Commonly on dorsal tongue, hard palate, inner aspect of lips – Often under ill-fitting or poorly cleaned denture

Pseudomembranous candidiasis n

– Any intraoral site – Commonly on buccal mucosa, soft palate and tongue



to dissolution. However, when saliva is acidi-fied, dissolution proceeds. It is recognized that lightly softened enamel may experience reminer-alization, particularly in the presence of fluoride [61]. This underscores the need for fluoride inter-vention in SS patients with low unstimulated flow rate.

Mucins are glycoproteins that provide mechanical protection to tissues, prevent dehydration and facilitate lubrication of food. The mucous glycoproteins of saliva, such as MUC5B, MUC7 and proline-rich glycopro-teins, play a major role in lubrication. This lubrication reduces trauma to soft tissues dur-ing mastication, swallowing and speaking. Primary SS patients with hypo salivation dis-play a decrease in the concentration of mucin, MUC5B and amylase [62]. These glycoproteins

also help maintain an intact layer of saliva (the salivary film) in contact with the oral mucosa, which prevents it from drying out. Salivary film thickness has been studied and reported to be thickest on the posterior tongue and thinnest on the hard palate. In patients experiencing dry mouth, the film thickness on the hard palate was thinner than 10 µm [63]. When salivary flow is low, areas of the mucosa become des-iccated, friable and much more susceptible to abrasion from foods, trauma from chewing and from ill-fitting dentures.

Dental decayXerostomia, or the subjective feeling of a dry mouth, is generally accompanied by hypo-salivation. Normal saliva is a rich fluid con-taining electrolytes, buffers to neutralize oral acidity and antimicrobial proteins to counter Streptococcus mutans, which is the main bacte-ria associated with dental decay. Hyposalivation will mean fewer buffering and flushing oppor-tunities for the oral hard tissues [64,65]. Lack of saliva may predispose to atypical dental decay observed on the cervical, incisal and radicular portions of the teeth [66]. Low salivary secre-tion promotes rapid formation of dental plaque. Due to early and often undetectable changes in salivary constituents that can promote tooth loss, it has been suggested that early dental loss may reflect a silent involvement of the salivary glands. Early changes in salivary biochemistry promoting dental decay may occur long before xerostomia [67,68].

Quality of lifeQuality of life is profoundly affected due to diminished ability to eat, speak, sing, socialize, sleep and be a productive member of the work force. Hence, oral dryness in SS is more than an inconvenience. Reports have suggested that physicians and dentists do not appreciate the oral–systemic connection and the contribution of oral symptoms to quality of life [69–72].

Detection of food taste is aided by the chemical reaction between saliva, tastants and taste recep-tors. The sensation and sensitivity of taste may be altered with diminished saliva. Oral taste buds are located in the epithelial folds of the foliate and circumvallate papillae, and fungiform papillae and soft palate. Taste substances dissolve in the salivary fluid layer to reach and stimulate taste receptors. In addition, the epidermal growth fac-tors in saliva may promote formation and renewal of taste buds. Low flow may affect food choices and compromise nutritional status [73].

Sjögren’s syndrome patients show lower sub-mandibular/sublingual flow rates and changed salivary composition of parotid and subman-dibular/sublingual saliva. Salivary changes make speech more difficult and may result in less willingness to engage in social interaction, and discomfort with interpersonal communica-tions. A reduction of salivary volume will com-plicate formation of a food bolus for swallow-ing, creating difficult social situations [74]. In SS patients, halitosis can also be a concern. In patients with a low unstimulated salivary flow rate, clearance of bacteria and desquamated

Figure 3. Labial salivary gland biopsy showing multifocal lymphocytic infiltration, consistent with Sjögren’s syndrome. Magnification: 5×.



epithelial cells is reduced greatly, increasing the tendency for halitosis. This may be especially problematic before breakfast as salivary flow is further reduced during sleep.

In a recent report of quality of life in a SS cohort, salivary flow rate was correlated sig-nificantly with both the Disease Damage Index published by Vitali et al. [75], and a standardized Oral Health Impact Profile (OHIP-14) [76]. The number of autoimmune symptoms was corre-lated with both oral and generic quality of life. Of note, oral health independently accounted for a significant percentage of variance in the generic Short Form-36 (SF-36) domains of general health and social function. The find-ings suggested that oral health has an indepen-dent influence on general quality of life beyond the effects accounted for by other autoimmune symptoms [72].

With increased awareness of the importance of oral health for patients with ‘dry mouth’, physicians can screen for oral disease, provide oral health education, initiate preventive and management strategies, and encourage patients to consult with their dentist for a complete oral evaluation.

Management of sequelaeHyposalivation The dental management for patients with SS is critical to their long-term oral health. While glandular damage cannot be restored, pro-active management to increase oral lubrication is important. Management of oral manifesta-tions includes intense oral hygiene, prevention and treatment of oral infections, use of saliva substitutes and local and systemic stimulation of salivary secretion. Cholinergic agents, such as pilocarpine and cevimeline, are helpful in patients with residual salivary function.

An important feature of having a continuous flow of unstimulated saliva into the mouth is that it reduces the probability that oral bacteria will be able to ascend the salivary ducts and create retrograde glandular infections.

Dental erosion & decayAs mentioned, patients demonstrating hypo-salivation will also demonstrate increased sus-ceptibility to dental decay. Enamel dissolution begins at a pH of approximately 5.5, but will vary depending on the concentrations of calcium and phosphate ions within the saliva. Fruit juices and carbonated drinks can be especially prob-lematic due to the sugar content and acidic pH [77]. The pH of common colas is approximately

2.5–3.4. Sports drinks and other beverages have been assessed as well. Coca-Cola® Classic pro-duced the lowest mean pH, while Starbucks® Frappucino produced the highest pH of any of the drinks except for tap water. Red Bull had the highest mean buffering capacity (indicating the strongest potential for erosion of enamel), followed by Gatorade®, Coca-Cola Classic, Diet Coke® and Starbucks Frappucino [78]. Buffering capacity and frequency of drinking are also sig-nificant. Reduced residence times of beverages in the mouth by salivary clearance or rinsing would appear to be beneficial [79]. Frequency of drinking is more significant, in that buffer-ing capacity cannot keep pace with the acidic insult. Dental erosion may also be caused by citrus abuse (sucking on citrus fruit or leaving citrus fruit in contact with tooth enamel for long periods) and the use of chewable vitamin C tab-lets. Dental erosion of the posterior teeth is an important finding with respect to the diagnosis of gastro-esophageal reflux disease (GERD). Reflux of acidic gastric fluids into the posterior part of the oral cavity can promote enamel dis-solution. Therefore, it is important for physicians to evaluate patients exhibiting dental erosion for acid reflux disease [80,81].

Home careFollow-up visits every 4 months may assist in monitoring and treating active dental caries. Patients should be educated and empowered to assist in the management of their own oral

Figure 4. Labial salivary gland biopsy showing chronic sclerosing sialadenitis. Magnification: 5×.



health. Salivary stimulants such as sugar-free gums and lozenges will assist in enhancing the salivary flow and are readily available. Xylitol-sweetened gums and lozenges are beneficial due to their reported anticariogenic effects [82]. The choice of product to stimulate saliva depends on individual preference [22]. Efficacy will vary with frequency of use and the amount of functional salivary gland tissue. Artificial saliva substitutes and oral hygiene products that contain lacto ferrin (e.g., Biotene® tooth-paste and mouth rinse) will also be helpful [83]. Toothpastes should contain fluoride and be nonabrasive, to better protect the enamel. Sodium lauryl sulfate-free toothpastes might be preferred, as this compound has been associated with hypersensitivities.

Meticulous home care is critical and should include a customized fluoride program. For maximum protection, patients should brush and floss following all sugar exposures and seek dental care every 4–6 months to moni-tor caries status. Dentist-applied fluoride var-nishes may deter progression of dental decay and decrease dentin sensitivity on exposed root surfaces. Topical fluoride gels, either brush-on or administered via custom-made carriers at bedtime, are important adjuncts for long-term dental health. Neutral sodium fluoride (1.1%) or 0.4% stannous fluoride have caries reduc-tion activity, but large-scale controlled trials in Sjögren’s patients have not been conducted to compare efficacy between the two agents. The

most important time for tooth brushing is just before bedtime, because salivary flow is negli-gible during sleep and the protective effects of saliva are lost [28,84].

SialogoguesIn addition to xylitol-sweetened lozenges and gums, prescription sialogogues, such as pilo-carpine and cevimeline, can be very helpful as long as functional salivary gland tissue remains. Studies have demonstrated objective improve-ment by increasing the rates of saliva and tear flow in SS patients, and/or subjective improve-ment of symptoms of dry mouth, dry eyes and overall dryness [85–89]. One study evaluated the efficacy of a hydrogel polymer buccal insert as a controlled-release delivery vehicle for pilo-carpine. The authors found that the insert delivered more than 85% of a 5-mg dose of pilocarpine hydrochloride with minimal side effects [90]. Prescription sialogogues are not recommended for all patients. They should not be used in patients with uncontrolled asthma

or narrow-angle glaucoma, and should be used with caution in certain types of cardiovascular disease and liver conditions.

Xerostomia-inducing medications Approximately 400 medications can induce some degree of salivary gland hypofunction [91,92]. These will include diuretics, α-adrenergic agents and antihypertensive agents such as β-blockers, calcium-channel blockers and angiotensin-converting enzyme inhibitors [93]. Anti-anxiety drugs and appetite suppressants may be prob-lematic as well. An important part of patient education concerns over-the-counter xerostomia-producing medications. Patients may be unaware that components of common antihistamines (pseudoephedrine) and sleep medications con-taining diphenhydramine hydrochloride will increase the severity of oral dryness.

Periodontal concernsNot only are SS patients more susceptible to dental decay and Candida, but their perio-dontal status should be monitored as well. While some reports indicate no significant difference between the periodontal status of SS patients and controls [94–97], others report more severe periodontitis in SS patients [98,99].

Restorative dentistry & surgical proceduresPatients should be given all assistance possible to maintain their dentition in the optimal con-dition. This includes the preventive therapy described above, as well as conservative restor-ative therapy geared towards long-term function in an environment with probable salivary hypo-function. In some patients, SS will be accom-panied by rheumatoid arthritis, resulting in a diminished ability to brush and floss teeth due to metacarpal/phalangeal changes and chronic pain. Periodontal therapy, fixed partial dentures and implant-supported prosthesis should be con-sidered in conjunction with systemic health, and sustainable oral comfort and esthetics. As saliva will be compromised, adapting to conven-tional removable dentures is often unsuccessful. Implant-retained bridges and dentures have been extremely successful in SS patients, with proper patient selection.

As many of these patients are taking bis-phosphonates for osteoporosis, the option of periodontal surgery, implant replacements for lost teeth and implant-supported dentures is one that should be approached with care and patient informed consent. While the potential



for bisphosphonate-associated osteonecrosis of the jaw in patients taking oral therapy is low, it is a concern. Concomitant prednisone or immuno-suppressive therapy will put the patient in a much higher risk group. No consensus has been reached to date precisely quantifying the degree of risk associated with bisphosphonates and den-tal therapy. In an ideal situation, surgical dental care would be completed prior to initiation of oral bisphosphonate therapy. However, this is not always feasible. Ongoing routine dental care is necessary for all SS patients, and must not be discontinued due to bisphosphonate therapy. However, the potential of bisphosphonate-asso-ciated osteonecrosis should be reviewed with SS patients prior to dental care, especially periapical or periodontal surgery, extractions and implant placement procedures [100–105].

CandidiasisDue to diminished concentration of anti fungal proteins normally found in saliva and the lack of mechanical flushing action that saliva provides, oral candidiasis is a concern. When the oral balance is altered, antifungal defenses are over-whelmed, and Candida may flourish. Candida albicans has been isolated from dental plaque in SS patients at higher prevalence than control sub-jects (73 vs 7%) despite good oral hygiene [106]. In another report, the prevalence of oral Candida varied according to the methods used to deter-mine the presence of the organism (49% positive with wet mount, and 77% positive with oral rinse cultures). A low stimulated salivary flow rate was associated with Candida carriage [107]. In another study, oral candidiasis was diagnosed in 74% of SS patients, versus 23% in the control group. Frequent symptoms were increased sensitivity to spicy foods (58%) and unpleasant metallic taste (40%). Common signs of oral candidiasis were erythematous lesions on the dorsum of the tongue (68%) and angular cheilitis (24%) [108]. If the patient complains of a ‘burning tongue’ and dysgeusia, oral candidiasis should be suspected. The incidence of oral candidiasis will increase with glucocorticoid-containing inhalers and systemic prednisone. Treatment includes topical antifungal therapy with nystatin oral suspension or tablets, or clotrimazole 10 mg oral troches four to five times per day for 2 weeks. For angular cheilitis, topical cream or ointment preparations applied to the commissures, in addition to tab-lets for intraoral topical treatment, is helpful. For persistent infections, systemic antifungal therapy such as fluconazole, 100 mg per day for 2 weeks, could be used.

When oral candidiasis is diagnosed, the patient should be instructed to purchase a new toothbrush in addition to appropriate topical or systemic therapy. Removable dentures frequently become infected with candidiasis and should be disinfected through vigorous brushing and soak-ing in commercial agents according to manufac-turer’s instructions. Patients should be discour-aged from wearing the dentures at night-time during sleep. Cleansing dentures in a solution of 1% sodium hypochlorite, or if they contain exposed metal, in a 1:750 dilution of benz-alkonium chloride, has been suggested [109].

Salivary gland enlargement & lymphomaSalivary gland enlargement, which often starts unilaterally, but becomes bilateral, can be chronic or episodic. Enlargement may be due to SS-related nonspecific inflammatory changes, sialolithiasis and retrograde sialadenitis. Additional considerations for bilateral enlarge-ment of the parotid and submandibular salivary glands include anorexia nervosa, bulimia, diabe-tes mellitus, hypothyroidism, alcohol-induced hepatic cirrhosis, HIV and hepatitis C [110–115].

When long-standing salivary gland enlarge-ment in SS suddenly increases in size or pain, imaging and biopsy are recommended. The dif-ferential diagnosis would include sialolithiasis, salivary gland tumor, low-grade mucosa-asso-ciated lymphoid tissue (MALT) lymphoma and aggressive non-Hodgkin’s lymphoma. Patients with SS have an increased risk of developing lymphoma [116–120]. Early literature reported that Sjögren’s patients have a 44-fold increase in the rate of lymphoma [119], but more recent reports have lowered the prediction to a 16-fold increased risk [121]. These tumors may arise in the salivary gland or within lymph nodes. What was formerly considered a ‘benign lymphoepithelial lesion’ in the parotid gland might currently be diagnosed as a low-grade non-Hodgkin’s B-cell lymphoma or mucosa-associated lymphoid tis-sue (MALT) lymphoma [122]. MALT is normally found in Peyer’s patches in the ileum of the lower gastrointestinal tract, where it plays a role in nor-mal humoral immune response. Mononuclear cell lymphocytic infiltrates in the exocrine glands can develop into marginal zone B-cell lesions or acquired MALT. A recent enlargement or persistent parotid enlargement [123] could be a lymphoma. MALT lymphomas have even been discovered though SS labial salivary gland biopsies [124]. Patients with SS have an increased risk of developing monoclonal B-cell MALT



lymphoma, perhaps due to prolonged autoim-mune inflammation or persistent antigenic stim-ulation to virus or bacteria. Occasionally, high-grade lymphomas develop that can demonstrate aggressive behavior. In a cohort of 723 primary SS patients, one in five deaths was attributable to lymphoma. The presence of palpable purpura and low C4 levels at the first visit adequately distinguishes high-risk patients (type I primary SS) from patients with an uncomplicated disease course (type II [low-risk] primary SS) [125].

Imaging of a salivary gland enlargement is essential for diagnosis and treatment [126,127]. The role of imaging is to define location, detect malignant features, assess local extension and invasion, and detect nodal metastases. A lym-phoma arising in the parotid gland has a clinical presentation similar to other neoplasms arising within the parotid gland. A CT scan is useful to determine the site and extent of the disease, loco-regional nodal status and contralateral gland and neck status. Multifocality and asso-ciated adenopathy are associated with, but not exclusive to, parotid lymphoma. Although poor tumor boundary definition on CT imaging is a strong predictor of malignancy, no patho-gnomonic finding specific for lymphoma has been identified.

For lesions arising in the superficial parotid and submandibular gland, ultrasound may be used for initial assessment. For lesions of the deep lobe of the parotid gland and minor sali-vary glands, MRI and CT are the modalities of choice. If deep-tissue extension is suspected or malignancy confirmed on cytology, an MRI or CT is mandatory to evaluate local invasion. For all tumors in the sublingual gland, MRI should be performed as the risk of malignancy is high [128]. Recently, a report on a proposed MR factor ana lysis using dynamic contrast-enhanced MRI on 35 salivary gland tumors indicated that the 2D distributions of the time–intensity curve (TIC) patterns correlated well with the histological features of the sali-vary gland tumors and allowed more detailed dynamic structures of tumors when compared with the results obtained by conventional dynamic study ana lysis [129].

Future therapiesSeveral potential therapies are in their early phases of utilization or undergoing active research. These include anti-T- and anti-B-cell therapies, gene transfer therapies and prote-omics, with a focus on salivary biomarkers that may ultimately lead to new therapies.

Anti T- & B-cell therapiesThe gain in knowledge regarding the cellular mechanisms of T- and B-lymphocytic activity in the pathogenesis of SS, and the current avail-ability of various biological agents (anti-TNF-α, IFN-α, anti-CD20 and anti-CD22) have resulted in new strategies for therapeutic intervention. Currently, B-cell-directed therapies seem to be more promising than T-cell-related therapies. However, large, randomized, placebo-controlled clinical trials are needed to confirm the promis-ing results of these early studies. When perform-ing these trials, special attention must be paid to prevent the occasional occurrence of severe side effects [130]. Anti-TNF agents (infliximab and etanercept) and B-cell targeted therapies (rituximab and epratuzumab) have been used in primary SS. In a well-controlled, double-blind clinical trial, anti-TNF therapy, infliximab, was reported to be ineffective in SS [131]. Anti-B-cell therapy is a potential treatment for the glandu-lar and extraglandular manifestations, including management of SS-associated lymphoma [132]. Anti-CD22 monoclonal antibody is expressed on the surface of normal mature and malignant B lymphocytes. It appears to be involved in the regulation of B-cell activation through B-cell receptor signaling and cell adhesion. It is comple-mentary to the known effects and role of CD20 antibodies. It may provide distinct therapeutic benefits for autoimmune diseases [133].

A recent study suggested that mizoribine could be an effective treatment for primary SS. Mizoribine is a nucleoside produced by Eupenicillium brefedianum with antibiotic, cytotoxic and immunosuppressive activity. Improvements were noted in salivary flow and a physician’s assessment of oral sicca symptoms, all measured using a 10-cm visual analogue scale [134]. One case has been reported with sud-den onset of diabetic ketoacidosis and acute pan-creatitis in a rheumatoid arthritis patient 2 weeks after introduction of mizoribine therapy [135].

Gene-transfer therapyResearch is being focused on implementing tis-sue-engineering principles combined with gene transfer and stem-cell methodologies to develop an artificial salivary gland device [136]. There is some optimism regarding restoring function to the damaged salivary gland [137]. Reports of experiments on animal models have revealed that the physical and biological characteristics of salivary glands provide unique advantages favor-ing successful gene transfer [138,139]. Considering such inherent advantages, the efficacy and safety



of applying gene transfer to salivary glands is believed to have extensive clinical value. The prospects seem promising to restore the salivary gland function by gene transfer to the gland in vivo.

Current clinical trials indicate that immuno-modulatory protein therapy can benefit patients with certain autoimmune diseases. The challenge to systemic protein therapies is ineffective admin-istration routes and systemic side effects. An alternative approach being investigated is devel-oping localized expression via gene therapy in the salivary glands. Genes encoding cyto kines or cDNAs encoding soluble forms of a key cytokine receptor can be introduced directly into the sali-vary glands. The expected outcome is alteration of immune response locally, but not systemically. Several gene targets are being examined [140].

ProteomicsRecent developments in proteomics have resulted in the identification of a large number

of different proteins, both in whole saliva and in secretions from individual glands. The tech-nique uses an initial separation of proteins by means of electrophoresis or chromatography, isolation of small groups of proteins or their con-stituent peptides, and after further separation by

means of chromatography, identification of the peptides via mass spectrometry. From a database of the peptides in known proteins, researchers can then identify the proteins present in saliva. Dr David Wong, of UCLA (CA, USA), has been a leader in this field. A recent study indi-cated that 16 proteins were downregulated and 25 were upregulated in SS patients compared with matched controls [141]. As the authors indicated, large-scale multi center clinical trials must be completed before use in clinical settings can be moved forward. It is expected that these biomarkers will be used for monitoring severity or progression of dysfunction and response to treatments. Much must be done, but the future is optimistic.

Executive summary

Clinical signs & symptomsClinical signs and symptoms may include xerostomia and hyposalivation dental decay, a desiccated, erythematous, fissured tongue, oral n

candidiasis and salivary gland enlargement.

DiagnosisDiagnosis will include subjective patient findings such as reported oral sicca, or the sensation of ‘dry mouth’ and positive responses to n

questions regarding oral dryness.

Objective diagnostic findings may include lack of salivary pooling in the floor of the mouth, and diminished whole unstimulated salivary n

flow rate, salivary gland enlargement, positive imaging of the major salivary glands, and a positive labial salivary gland biopsy.

ManagementManagement of oral manifestations will include supportive care such as salivary stimulants and oral lubricants, frequent dental visits n

with meticulous patient oral hygiene, a customized fluoride program and nutritional counseling. Due to the impact of oral manifestations on quality of life, patient education is important to empower patients to participate in their own care.

Future therapiesFuture therapies include anti-T- and anti-B-cell therapies, gene transfer therapies and proteomics.n

BibliographyPapers of special note have been highlighted as:n of interestnn of considerable interest

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AffiliationsCarol M Stewart, MS, DDS, MS n

Department of Oral and Maxillofacial Surgery and Diagnostic Sciences University of Florida Center for Orphaned Autoimmune Disorders, PO Box 100414, JHMHC, University of Florida College of Dentistry, Gainesville, FL 32610, USA Tel.: +1 352 392 6775 Fax: +1 352 392 2507 [email protected]

Kathleen Berg, PhD n

University of Florida Center for Orphaned Autoimmune Disorders, PO Box 100414 JHMHC, Department of Oral and Maxillofacial Surgery and Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL 32610, USA



Oral manifestations of Sjögren’s syndrome

Activity evaluation: where 1 is strongly disagree and 5 is strongly agree.

1 2 3 4 5

The activity supported the learning objectives.

The material was organized clearly for learning to occur.

The content learned from this activity will impact my practice.

The activity was presented objectively and free of commercial bias.

1. Which of the following is least likely to be a common manifestation of Sjögren’s syndrome (SS)?

£ A Dry eyes

£ B Dry skin

£ C Dry mouth

£ D Fatigue

2. Which of the following best describes the prevalence of systemic extraglandular manifestations of SS?

£ A 20%

£ B 30%

£ C 40%

£ D 50%

3. SS is least likely to be associated with which one of the following conditions?

£ A Multiple sclerosis

£ B Rheumatoid arthritis

£ C Scleroderma

£ D Primary biliary sclerosis

To obtain credit, you should first read the jour-nal article. After reading the article, you should be able to answer the following, related, mul-tiple-choice questions. To complete the ques-tions and earn continuing medical education (CME) credit, please go to http://cme.medscape.com/public/futuremedicine. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.com. If you are not registered on Medscape.com, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited

provider, [email protected]. For technical assistance, contact [email protected]. American Medical Association’s Physician’s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activi-ties. For further information on this award, please refer to http://www.ama-assn.org/ama/pub/category/2922.html. The AMA has determined that physicians not licensed in the US who par-ticipate in this CME activity are eligible for AMA PRA Category 1 Credits™. Through agree-ments that the AMA has made with agencies in some countries, AMA PRA credit is acceptable as evidence of participation in CME activities. If you are not licensed in the US and want to obtain an AMA PRA CME credit, please complete the questions online, print the certificate and present it to your national medical association.

4. Which of the following is least likely to be a criterion of the European–American Consensus Group for the diagnosis of SS?

£ A Ocular signs

£ B Salivary gland biopsy findings

£ C Presence of another autoimmune disease

£ D Presence of serum autoantibodies

5. Which of the following infections is of most concern in patients with SS?

£ A Oral herpes simplex virus

£ B Oral candidiasis

£ C Mumps virus

£ D Streptococcal B infection

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